The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis

BACKGROUND: Osteoporosis affects approximately 10 million people in the United States and is associated with increased fracture risk and fracture-related costs. Poor adherence to osteoporosis medications is associated with higher general burden of illness compared with optimal adherence. OBJECTIVES: To examine the associations of adherence to osteoporosis therapies with (a) occurrence of closed fracture, (b) all-cause medical costs, and (c) all-cause hospitalizations. METHODS: This retrospective analysis of administrative claims data examined women with osteoporosis initiating therapy with alendronate, risedronate, ibandronate, or raloxifene from July 1, 2002, to March 10, 2006. Data were from a large, geographically diverse U.S. health plan that covered about 12.6 million females during the identification period. Commercially insured and Medicare Advantage plan enrollees were observed for 1 year before (baseline period) and 540 days after therapy initiation (follow-up period). Outcomes included closed fractures, all-cause medical costs, and all-cause hospitalizations; all outcomes were measured starting 180 days after therapy initiation through follow-up. All subjects had at least 2 pharmacy claims for any of the targeted osteoporosis medications. Adherence was measured with a medication possession ratio (MPR) and accounted for all osteoporosis treatment. High adherence was MPR of at least 0.80; low adherence was MPR less than 0.50. Covariates included baseline fracture, early fracture (in the first 180 days of follow-up), baseline corticosteroid or thyroid hormone use, health status indicators, and demographic characteristics. Outcome fractures were modeled with Cox survival regression with time-dependent cumulative MPR. All-cause medical costs and all-cause hospitalizations were modeled, respectively, with generalized linear model regression (gamma distribution, log link) and negative binomial regression. RESULTS: The sample comprised 21,655 patients 16,295 (75.2%) commercial and 5,360 (24.8%) Medicare Advantage. During the entire follow-up period, 5,406 (33.2%) and 2,253 (42.0%) of commercial and Medicare Advantage patients, respectively, had low adherence. Adherence tended to decrease over the follow-up period. The Cox regression showed that commercial plan patients with low versus high adherence had 37% higher risk of fracture (hazard ratio=1.37, 95% CI=1.12-1.68). Adherence was not significantly associated with fracture in the Medicare Advantage cohort. Commercial and Medicare Advantage patients with low versus high adherence had 12% (exponentiated coefficient=1.12, 95% CI=1.02-1.24) and 18% (exponentiated coefficient=1.18, 95% CI=1.04-1.35) higher all-cause medical costs during months 7 through 18 of follow-up. Commercial and Medicare Advantage patients with low versus high adherence had 59% (incidence rate ratio [IRR]=1.59, 95% CI=1.38-1.83) and 34% (IRR=1.34, 95% CI=1.13-1.58) more all-cause hospitalizations during months 7 through 18 of follow-up, respectively. CONCLUSIONS: Low adherence to osteoporosis pharmacotherapy was associated with higher risk of fracture for commercially insured but not Medicare Advantage patients and with higher all-cause medical costs and more all-cause hospitalizations in both groups. These results are consistent with the literature and highlight the importance of promoting better adherence among patients with osteoporosis.


R E S E A R C H
• Compared with previous research, the present study provides a more contemporary population from a large, geographically diverse health plan, allowing the inclusion of newer and lessexamined therapies (ibandronate, raloxifene) and health care costs (not charges). • Compared with high adherence (MPR of at least 0.80), low adherence (MPR less than 0.50) was associated with 37% higher likelihood of fracture in commercial patients after controlling for demographic, clinical, and fracture risk factors. High adherence was not associated with fracture risk in Medicare Advantage patients. • For commercially insured and Medicare Advantage patients, respectively, regression-adjusted low adherence versus high adherence was associated with 12% and 18% higher all-cause medical costs and 59% and 34% more all-cause hospitalizations.
The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis of a hip fracture and 39.9% lower odds of vertebral fracture within a year of initiation of osteoporosis therapy. 13 Siris et al. estimated the 24-month risk of fracture along the full spectrum of MPR values from 0.0 to 1.0 and found, importantly, that the regression-adjusted risk of fracture among women who were less than 50% adherent was substantially the same as the risk of fracture associated with no therapy. 7 Fractures can result in wide-ranging health care resource utilization and costs beyond the direct costs attributable to acute fracture treatment and follow-up. Osteoporotic fractures may also be associated with depression, functional impairment, cognitive impairment, pain, disability, and decline in lung function. [15][16][17] Patients whose fractures are treated in inpatient facilities may require subsequent hospitalization for post-operative complications, such as chest infection, cardiac failure, deep vein thrombosis, 18 or pneumonia. Moreover, there are costs associated with osteoporosis that are not specific to fracture, such as physician visits and bone density scans.
Huybrechts et al. found that nonadherence to osteoporosis therapy was associated with a 37.2% higher rate of all-cause hospitalizations per patient-month and higher mean total health care charges ($600 vs. $340 per patient per month, P < 0.001). 8 Sunyecz et al. showed that total medical costs were 3.5% lower for patients who were adherent on bisphosphonates compared with their nonadherent counterparts. 14 Adherent patients (defined as those with 360 days of continuous therapy in the first year after therapy initiation) in the study by McCombs et al. had lower expenditures for physician services during the first year of therapy (U.S. $56 lower than nonadherent patients), hospital outpatient services ($38 lower), laboratory tests ($9 lower), and hospitalizations ($155); adherent patients also had 25.6% lower odds of hospital admissions compared with nonadherent patients. 13 Although multiple studies have examined the relationship between osteoporosis therapy adherence and fracture, relatively few have examined the broader relationships with costs and hospitalizations (a substantial cost driver). The purpose of this study was to examine clinical, economic, and health resource utilization consequences of osteoporosis in a sample that was updated and diverse.
This study provides several new contributions to the literature. First, the study period is contemporary and includes the more recently approved ibandronate, a monthly bisphosphonate; patient identification periods for the studies described above ranged from 1997 to 2003, and therapies did not include ibandronate. Moreover, raloxifene, a therapy not commonly studied, 13 is included as 1 of the targeted osteoporosis therapies. Second, the costs in this study were computed from health plan and patient paid amounts, rather than from charges; charges may not accurately reflect the dollars expended for medical services. Third, this study separately analyzed outcomes in 2 O steoporosis is characterized by loss of bone mass and a structural deterioration of bone tissue. 1 Reduced bone density associated with osteoporosis is a major risk factor for fracture, most notably of the hip, spine, and wrist. 2,3 Epidemiological data show that an estimated 10 million people in the United States (8 million women) are diagnosed with osteoporosis. Another 34 million individuals have osteopenia (low bone density) that does not meet the criteria for osteoporosis. 2 One-half of women and 25% of men aged 50 years or older will suffer from an osteoporosis-related fracture in their lifetimes. 2,3 Fractures resulting from bone disease are common and impose a substantial societal burden. 3 Burge et al. (2007) estimated direct medical costs of osteoporosis in the United States at 13.7-20.3 billion in 2005 dollars. 4 They also modeled U.S. fracture rates and costs until 2025, resulting in estimates of more than 3 million fractures and expenditures of $25.3 billion per year by 2025. 4 Therapies currently approved in the United States for the treatment of osteoporosis include bisphosphonates (alendronate, ibandronate, risedronate, and zoledronic acid), the selective estrogen receptor modulator raloxifene, calcitonin, and the parathyroid hormone teriparatide. 5 Bisphosphonates are approved for the prevention and treatment of postmenopausal osteoporosis. Raloxifene is approved for use in postmenopausal women to treat or prevent osteoporosis and to reduce the risk of invasive breast cancer among those with osteoporosis. Estrogen/hormone therapy is approved for the prevention of osteoporosis. 5 Teriparatide is an injectable form of human parathyroid hormone indicated for postmenopausal women and men at high risk for osteoporotic fracture. 5 Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANKL), was approved by the U.S. Food and Drug Administration in 2010 for treatment of postmenopausal women with osteoporosis who have a high risk of fracture; it is injected subcutaneously every 6 months. 6 "Real-world" adherence to osteoporosis medications tends to be suboptimal.  14 showed that less than 50% of osteoporotic women treated with daily and weekly bisphosphonates (with bisphosphonates or hormone replacement therapy in the study by Huybrechts et al.) were adherent to their medication regimens; adherence in all studies was defined as a medication possession ratio (MPR) of at least 80%. 7,8,11,14 Nonadherence with osteoporosis therapy has been associated with increased fracture risk. 7-10,12, 13 Huybrechts et al. found that nonadherence (MPR less than 80%) was significantly associated with a 16.7% higher risk of fracture. 8 McCombs et al. (2004) modeled adherence rather than nonadherence and showed that adherence was associated with 61.8% lower odds discrete populations: women enrolled in the commercial health plan, and women enrolled in the Medicare Advantage health plan. This approach was adopted principally because these populations are distinct with respect to health care delivery, reimbursement, and payers. Although it was beyond the scope of this study to examine the associations between the outcomes and characteristics of the health care delivery systems, we believe that separate analysis of the commercial and Medicare Advantage populations provides more information-information that would be useful in generating questions for further research-than would analyzing the populations together and controlling for health plan type in multivariate analysis.

Objectives
The objectives of this study were to examine the associations of adherence to osteoporosis medications with (a) occurrence of closed fracture, (b) all-cause medical costs, and (c) all-cause hospitalizations. All-cause medical costs and hospitalizations were measured to reflect the more pervasive consequences both of fracture and osteoporosis more generally.

■■ Methods Study Design and Data Source
This was a retrospective analysis of administrative claims data that examined adherence, fracture, total all-cause medical costs including plan and patient share, and all-cause inpatient stays for women diagnosed with osteoporosis and initiated on osteoporosis therapy. The data included medical claims, pharmacy claims, and eligibility information from a large, national U.S. health plan that offers both commercial and Medicare Advantage insurance. The individuals covered by this health plan, about 14 million per year, are geographically diverse across the United States, with greatest representation in the South and Midwest U.S. census regions. The plan provides full insurance coverage for professional (e.g., physician), facility (e.g., hospital), and outpatient prescription medication services. Medical (professional, facility) claims include International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes, ICD-9-CM procedure codes, Current Procedural Terminology, Version 4 (CPT-4) procedure codes, Healthcare Common Procedure Coding System (HCPCS) procedure codes, site of service codes, health plan and patient costs, and coordination of benefits adjustment. Outpatient pharmacy claims provide National Drug Code (NDC) numbers for dispensed medications, quantity dispensed, drug strength, days supply, health plan and patient costs, and coordination of benefits adjustment. All study data were de-identified and accessed with protocols compliant with the Health Insurance Portability and Accountability Act; expedited review by the Privacy Board associated with the New England Institutional Review Board was conducted, and this research project was approved on April 25, 2008.

Patient Identification
The study sample included women who were aged 45 years or older, diagnosed with osteoporosis, and initiated on alendronate, ibandronate, raloxifene, or risedronate. All patients had at least 1 medical claim with a primary or secondary diagnosis of osteoporosis (ICD-9-CM 733.0x) during the identification period of July 1, 2002, through March 10, 2006, and at least 2 pharmacy claims for any of the following osteoporosis therapies following the first observed claim with an osteoporosis diagnosis: alendronate (5 milligram [mg], 10 mg, 35 mg, 70 mg), ibandronate, raloxifene, or risedronate (5 mg, 35 mg). Medications were identified with NDC numbers. Examination of all pharmacy claims for the bisphosphonates showed that 96.2% of risedronate claims were for weekly risedronate, 97.2% of claims for alendronate were for weekly alendronate, and 99.2% of claims for ibandronate were for monthly ibandronate. The service date of the first pharmacy claim for a designated osteoporosis medication was defined as the index date and the medication was the index therapy. The criterion of at least 2 osteoporosis therapy claims was imposed to focus on women who were treated for a minimum time while allowing for variation in adherence.
In addition, patients were continuously enrolled, with medical and pharmacy benefits, in the commercial or Medicare Advantage plan for 12 months before the index date (baseline period) and 540 days after the index date (follow-up period) and had no pharmacy claims for alendronate, ibandronate, raloxifene, risedronate, or teriparatide during their baseline periods. The 540-day follow-up period was selected to allow the osteoporosis medications to achieve their therapeutic effects over the first 180 days and then to observe the study sample for 1 year (i.e., 12 consecutive 30-day intervals) after those first 180 days. The entire study period was from July 1, 2001, the earliest start date of the baseline period, through August 31, 2007, the latest end date of the follow-up period.
Patients with any pharmacy claims for alendronate with 40 mg strength (indicated for Paget's disease of the bone), risedronate with 30 mg strength (indicated for Paget's disease of the bone), or calcitriol (indicated for hypocalcemia) anytime during the baseline or follow-up periods were excluded in order to focus on patients treated specifically for osteoporosis. Patients with other conditions treated with the study medications were also excluded. Those conditions were Paget's disease of the bone and other osteitis deformans and osteopathies, osteogenesis imperfecta, hypercalcemia, malignant cancer, human immunodeficiency virus (HIV), and preventive treatment for breast cancer (Appendix).

Variables
The study outcomes were closed fracture, all-cause medical costs, and all-cause hospitalizations. Closed fractures were identified with primary or secondary diagnosis codes, The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis ICD-9-CM procedure codes, or CPT codes on at least 1 medical claim (Appendix); the codes were based largely on previous work by Huybrechts et al. (2006) 8 and Weycker et al. (2008). 10 The occurrence of an outcome fracture was defined as at least 1 medical claim with a fracture code, a service date 180 days or more after the index date, and no medical claims with fracture codes in the same fracture site for at least the previous 6 months in order to capture new fractures. The 180-day post-index date criterion was imposed to provide time for the osteoporosis therapies to achieve their therapeutic effects. The check for previous fractures at the same site was used to avoid misclassifying ongoing care for a previous fracture as a new fracture. 19 All-cause medical costs were the sum of health plan and patient paid amounts for all medical claims from 180 days following the index date through the end of the follow-up period. Costs were adjusted to 2006 dollars using the medical care component of the Consumer Price Index and were adjusted for coordination of benefits based on estimated payments from other payers. The third outcome was the number of all-cause inpatient hospitalizations from 180 days after the index date through the end of the follow-up period. Hospitalizations were measured with a combination of revenue codes and American Hospital Association place-of-service codes.
Adherence was measured with an MPR based on pharmacy claims for any of the designated osteoporosis medications (i.e., both index and nonindex therapies); the objective was to measure the overall impact of osteoporosis therapy, 8 although adherence to the index therapy was also examined. MPR was calculated by dividing the cumulative days supply of osteoporosis medication(s) by the number of days of follow-up. For MPR measured through the entire follow-up period, the denominator was 540 days. Cumulative days supply represents the number of days during the follow-up period when the patients were in possession of their medications; days during which patients possessed more than 1 osteoporosis therapy were counted only once. We assumed that osteoporosis medications were provided to patients during inpatient hospitalizations and adjusted the MPR numerator to account for prescription fills that were interrupted by inpatient stays. 8 Continuous MPR was converted to a categorical variable: "high" adherence was MPR of at least 0.80, 20,21 "moderate" adherence was MPR of at least 0.50 and less than 0.80, and "low" adherence was MPR less than 0.50. 7 Binary indicators of fracture risk included early fracture and baseline fracture. Early fracture was defined as at least 1 medical claim with a fracture code and service date during the first 180 days of follow-up including the index date. 8 Baseline fracture was defined as at least 1 medical claim with a fracture code and service date during the baseline period. 8 Drug-related fracture risk during the baseline period identified patients either with oral steroid use, defined as at least 2 pharmacy claims and at least 30 cumulative days supply of corticosteroids, or with thy-roid hormone use, defined as at least 1 fill of a thyroid hormone during the baseline period (Appendix).
Health status variables, measured during baseline, included an administrative claims-based Charlson Comorbidity Index (CCI) score; 22 number of medications defined as unique chemical compounds (e.g., simvastatin would be counted as 1 medication whether the NDC number was for Zocor or for generic simvastatin), not including targeted osteoporosis medications, used during baseline as a measure of polypharmacy; and binary indicators for nontraumatic joint disorders; spondylosis, intervertebral disc disorders, and other back problems; other connective tissue disease; other bone disease and musculoskeletal deformities; disorders of lipid metabolism; eye disorders; respiratory infection; and diseases of female genital organs. All binary health status indicators were computed from the diagnosis-based Clinical Classification Software managed by the Agency for Healthcare Research and Quality. 23 The conditions were selected based on clinical relevance to the outcomes and prevalence within the study population and were distinct from the conditions represented in the CCI. Demographic variables were age and U.S. census region.

Statistical Analysis
Descriptive summary statistics were obtained for all study measures. Commercial and Medicare Advantage patients were analyzed separately. The focus of the analysis was the difference in outcomes between patients with low and high adherence. Patients with moderate adherence and indicators for moderate adherence were included in all analyses. Differences in mean values were tested with t-tests for independent samples, accounting for unequal variance as appropriate. Differences in categorical variables were evaluated with Pearson chi-square tests.
Outcome fractures were analyzed with Cox survival regression with time-dependent cumulative adherence. 8 The dependent variable was time to the first observed outcome fracture. Patients' adherence levels (low, moderate, high) were calculated from the index date in cumulative 30-day intervals, and the appropriate cumulative adherence was applied to each observed outcome fracture. For example, if a patient had MPR = 1.0 in the first 30 days of follow-up and MPR = 0.70 during days 31-60 of follow-up, the cumulative MPR for the first 60 days of followup would be 0.85. If this patient's MPR during days 61-90 of the follow-up period were 0.70 again, the cumulative MPR for the first 90 days of follow-up would be 0.80. This process of computing and updating cumulative MPR continued for each patient throughout the length of follow-up. When a fracture occurred, the cumulative MPR for the period preceding the fracture was applied; for instance, if a fracture occurred on day 220 of a patient's follow-up period, the cumulative MPR through day 210 would be the time-dependent covariate.
Two specifications of this model were estimated. The first specification (bivariate model) had only 2 covariates, The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis time-dependent low adherence and time-dependent moderate adherence, in order to estimate the adjusted bivariate relationship between cumulative time-dependent adherence and fracture. The second specification (full model) also controlled for demographic characteristics, health status characteristics, and fracture risk factors (Table 1). Coefficients were computed as hazard ratios (HRs).
All-cause medical costs from 180 days after the index date through the end of follow-up (i.e., from the seventh through eighteenth 30-day intervals of follow-up) were modeled with a generalized linear model (GLM) with gamma distribution and log link. This period was selected to be consistent with the period during which outcome fractures were measured and to model all-cause medical costs after the time needed for the osteoporosis medications to achieve their therapeutic effects. The gamma distribution was selected based on the results of the Park test. 24 Coefficients were exponentiated to provide a ratio of costs for each covariate. Covariates are shown in Table 1.
All-cause inpatient hospitalizations from 180 days after the index date through the end of the follow-up period (same rationale as all-cause medical costs and outcome fractures) were modeled with negative binomial regression; negative binomial was selected as the estimator based on dispersion of the data (P < 0.001 in the likelihood ratio test of α = 0). Coefficients were computed as incidence rate ratios (IRRs). Covariates are listed in Table 1.
All analyses were conducted with SAS version 9 (SAS Institute, Inc., Cary, NC) and Stata version 10 (StataCorp LC, College Station, TX). The a priori α value of 0.05 was used for all analyses.

■■ Results
The study sample included 21,655 patients, 16,295 (75.2%) from the commercial plan and 5,360 (24.8%) from the Medicare Advantage plan. Figure 1 shows subject selection and attrition. Mean (standard deviation [SD]) ages for commercial and Medicare Advantage plan patients, respectively, were 59.3 (8.6) and 75.7 (6.5) years. Summary statistics for demographic, health status, and fracture risk factor measures are provided in Table 2. In both the commercial and Medicare Advantage groups, patients with high adherence were significantly more likely than those with low adherence to have a CCI score equal to zero (commercial: 73.7% vs. 66.6%, respectively; Medicare Advantage: 55.6% vs. 49.1%, respectively; both P < 0.001).
Approximately 88% of patients in both the commercial and Medicare Advantage groups used only 1 of the 4 selected therapies throughout follow-up (data on individual therapies not shown in tables). Alendronate was the most prevalent therapy, used by 45.3% of commercial patients and 50.1% of Medicare Advantage patients. Risedronate was the next most frequently observed therapy (31.9% of commercial patients, 25.5% of Medicare Advantage patients). Ibandronate was used by 3.2% and 2.4% of commercial and Medicare Advantage patients, respectively. Raloxifene was the osteoporosis therapy for The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis therapies over their follow-up periods; 33.2% (n = 5,406) and 42.0% (n = 2,253) of commercial and Medicare Advantage patients, respectively, had low adherence (MPR less than 0.50). Adherence, on average, declined over the follow-up period, as shown in Figure 2. For the first 180 days and subsequent 360 days (days 181-540) of follow-up in the commercially insured group, mean (SD) MPRs were 0.76 (0.25) and 0.59 (0.36), respectively. The corresponding MPRs in the Medicare Advantage group were 0.68 (0.28) during the first 180 days of follow-up and 0.53 (0.37) during the next 360 days (data not shown in tables).
Adherence in the commercial group appeared to be fairly consistent across individual osteoporosis therapies: 32.0% of commercial patients had low adherence on alendronate; 30.0% on ibandronate; 31.8% on raloxifene; 31.4% on risedronate; and 43.3% on multiple osteoporosis therapies. Adherence to individual therapies varied somewhat among Medicare Advantage patients: 42.7%, 28.5%, 37.9%, 44.0%, and 41.1% had low adherence on alendronate, ibandronate, raloxifene, risedronate, and multiple therapies, respectively (data not shown in tables). Table 3 provides the summary values of the outcome measures overall and for each adherence subgroup based on MPR during the entire follow-up period. The rates of outcome fractures (i.e., fractures that occurred at least 180 days after the index date) were 3.2% (n = 520) in the commercial group (3.0% vs. 3.6% for patients with high vs. low adherence, respectively, P = 0.044) and 5.9% (n = 318) in the Medicare Advantage group (5.8% vs. 6.2% for patients with high vs. low adherence, respectively, P = 0.601).
The majority of patients (93.1% of commercial, 84.1% of Medicare Advantage) had no (zero) outcome hospitalizations (all-cause hospitalizations from 180 days after their index dates through the end of their follow-up periods). Commercial plan patients with high adherence were more likely to have no (zero) outcome hospitalizations compared with patients with low adherence (94.5% vs. 91.3%, respectively, P < 0.001); 86.4% of Medicare Advantage patients with high adherence versus 82.3% of those with low adherence had no outcome hospitalizations (P = 0.004). Mean (SD) all-cause medical costs after the first 180 days of follow-up were $4,824 ($13,875) and $5,329 ($11,769) in the commercial and Medicare Advantage groups, respectively. Mean all-cause medical costs after the first 180 days of follow-up were lower among patients with high adherence in both groups relative to patients with low adherence. Mean (SD) all-cause medical costs for commercial plan patients with high and low adherence, respectively, were $4,295 ($13,179) and $5,596 ($15,291, P < 0.001). Mean (SD) all-cause medical costs were $4,590 ($10,797) for Medicare Advantage patients with high adherence versus $5,801 ($12,378) for those with low adherence (P < 0.001).
Results from the Cox survival regression with time-dependent adherence showed that commercial patients with low 7.0% of commercial patients and 9.7% of Medicare Advantage patients. About 12% of each group used more than 1 therapy during their follow-up periods (because adherence was based on any osteoporosis medication use, the combinations of therapies were not tracked).
Only 42.7% (n = 6,955) of commercially insured patients and 33.7% (n = 1,804) of Medicare Advantage patients were highly adherent (MPR of at least 0.80) to their osteoporosis    22

claims-based adaptation of Charlson score measured during 1-year baseline (pre-index) period. e Baseline health status conditions show numbers and proportions of patients with designated conditions based on diagnosis-based Clinical Classification Software managed by the Agency for Healthcare Research and Quality 23 and measured during 1-year baseline (pre-index) period. f Fracture risk factors show numbers and proportions of patients with fracture-related diagnoses or procedures in Appendix. Baseline is 1-year pre-index; early is first 180 days of follow-up period, including index date. g Baseline corticosteroid or thyroid hormone use shows numbers and proportions of patients with corticosteroid or thyroid hormone use measured with agents shown in Appendix during 1-year baseline (pre-index). CCI = Charlson Comorbidity Index; MPR = medication possession ratio; SD = standard deviation.
adherence were more likely than were patients with high adherence to have an outcome fracture ( Table 4). The bivariate models of fracture and time-dependent cumulative adherence indicate that commercial patients with low adherence were 42% more likely than were those with high adherence to have a fracture (HR = 1.42, 95% confidence interval [CI] = 1.17-1.74, P < 0.001). When the covariates were controlled, low adherence among commercial patients was associated with a 37% higher fracture risk (HR = 1.37, 95% CI = 1.12-1.68, P = 0.002). The HRs for low adherence in the Medicare Advantage group and for moderate adherence in both groups were not significant in any model. In addition, early fracture, baseline fracture, baseline CCI score, and baseline spondylosis, intervertebral disc disorders, and other back problems were significantly and positively associated with increased likelihood of fracture in both groups. Age 65 years or older was positively associated with the risk of fracture compared with age younger than 55 years in the commercial group; the HR for age 75 years or older compared with age younger than 75 years was not significant in the Medicare Advantage group.
In the GLMs, low osteoporosis therapy adherence throughout follow-up was associated with significantly higher all-cause medical costs after the first 180 days of follow-up relative to high adherence (Table 5). Low adherence compared with high adherence was associated with 12% higher medical costs (exponentiated coefficient = 1.12, 95% CI = 1.02-1.24, P = 0.022) in the commercial group and with 18% higher medical costs (exponentiated coefficient = 1.18, 95% CI = 1.04-1.35, P = 0.012) in the Medicare Advantage group. Moderate adherence compared with high adherence was also significantly and positively associated with higher all-cause medical costs after the first 180 days of follow-up in the Medicare Advantage group (exponentiated coefficient = 1.21, 95% CI = 1.04-1.40, P = 0.015), but was not significant in the commercial group. Baseline number of medications, baseline CCI score, baseline spondylosis, intervertebral disc disorders and other back problems, and age (65 years or older compared with younger than 55 for commercial patients and 75 years or older compared with younger than 75 years for Medicare Advantage patients) were significantly and positively associated with all-cause medical costs after the first 180 days of follow-up for both groups.
In negative binomial regression models, low adherence compared with high adherence was associated with more all-cause hospitalizations after the first 180 days of and higher all-cause medical costs compared with high adherence (MPR of at least 0.80). Low adherence was also associated with a significantly higher fracture risk, 37% higher compared with high adherence, in the commercial group. These results are largely consistent with the literature and published reviews on adherence and risk of fracture in osteoporosis. 7-10,13,25-29 A recent systematic review evaluated the impact of adherence to osteoporosis medications, principally bisphosphonates, on fracture rates in 17 published studies and reported a fracture risk reduction of 17% to 39% in patients who achieved an MPR of at least 0.80. 30 The HR for low adherence was not significant in the outcome fracture model for the Medicare Advantage group. The adherence model results are consistent with the descriptive results for the Medicare Advantage group ( Table 3) that show no significant differences in the rates of closed fracture across adherence categories. A recent study of Medicare beneficiaries enrolled in a Pennsylvania pharmacy coverage assistance program found that high adherence to oral bisphosphonates, defined as proportion of days covered of at least 0.80, was associated with 23% and 26% reductions in hip and vertebral fractures, respectively. 31 There is not, however, a large body of research focusing specifically on osteoporosis medication adherence and fracture among elderly subjects, and no research, to the best of our knowledge, that focuses on patients who forgo traditional fee-for-service Medicare and enroll in follow-up (Table 6). Commercial patients with low adherence had 59% more hospitalizations (IRR = 1.59, 95% CI = 1.38-1.83, P < 0.001), and Medicare Advantage patients with low adherence had 34% more hospitalizations (IRR = 1.34, 95% CI = 1.13-1.58, P = 0.001) compared with patients with high adherence. Commercial patients with moderate adherence had 29% more hospitalizations (IRR = 1.29, 95% CI = 1.10-1.52, P = 0.002) relative to those with high adherence, but the IRR for moderate adherence was not significant in the Medicare Advantage group (P = 0.058). Other positive and significant predictors for both groups were hospitalizations within the first 180 days of follow-up, baseline corticosteroid or thyroid hormone use, baseline CCI score, baseline respiratory infections, baseline spondylosis, intervertebral disc disorders or other back problems, and older age.

■■ Discussion
This retrospective analysis of women initiated on osteoporosis therapies was conducted with administrative claims data from one of the largest health plans in the United States and evaluated the association of adherence with several clinical and economic outcomes. Differences in outcomes between patients with low and high adherence were examined. The results establish that low adherence to osteoporosis therapy, defined for this study as MPR less than 0.50, was consistently associated with significantly more all-cause hospitalizations The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis    better elucidate these relationships.

P values compare the high-versus low-adherence groups using t-tests for independent samples for continuous variables and Pearson chi-square tests for categorical variables. b Outcome fractures were measured with diagnosis or procedure codes in the Appendix from 180 days after index date through end of follow-up period. c All-cause hospitalizations show numbers and proportions of patients with designated number of all-cause hospitalizations from 180 days after index date through the end
Consistent with published reviews, 30,32 a substantial portion of the patient sample-33% to 42%-was nonadherent with osteoporosis therapy. Our data also show that adherence tended to decrease over time. Proportions of patients with low adherence appeared to be descriptively similar across weekly and monthly bisphosphonates, particularly in the larger commercial group. This result may be inconsistent with the favorable adherence profile of monthly bisphosphonates over weekly bisphosphonates reported in a previous retrospective study. 33 Poor medication adherence is a common problem in the treatment of many chronic conditions and is attributable to many factors at the patient, physician, and health care sys-Medicare Advantage plans.
Low adherence to osteoporosis therapy was associated with significantly more all-cause hospitalizations and higher allcause medical costs after the first 180 days of follow-up in both the commercial and Medicare Advantage groups, consistent with prior research. 8,13,14 These relationships may be attributable to clinical consequences associated with fracture, such as depression and pain; additional care related to fracture-related hospitalizations, such as rehospitalization for pneumonia; and to broader patterns of care for osteoporosis. They also may be indications of the impact of unobserved health behaviors (e.g., adherence to all prescribed medications, general health-seeking and maintenance behaviors). Further research is needed to The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis adherence, the likelihood of closed fracture, or both. Examples of important unobserved factors include clinical measures not observed in claims, such as bone mineral density measures, and patient health behaviors. In addition, the hospitalization and cost outcomes investigated in this study were not specific to fracture. While providing valuable information, these analyses do not account as thoroughly as they might for other factors that influence these outcomes, so the effects of adherence to osteoporosis medications are likely conflated with other effects.
Second, we excluded individuals with only 1 pharmacy tem levels. 34 Although many empirical studies have evaluated osteoporosis therapy adherence from the patient perspective, data from the physician perspective are sparse. Future studies should examine the timing of patient-physician interactions and their relationship with adherence, therapy modifications, and outcomes.

Limitations
There are inherent limitations associated with research conducted with administrative claims data. First, unobserved and unmeasured factors may have influenced the likelihood of The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis therapies in the study sample. Typically, patients switch medications because of some problems with their initial therapies (e.g., side effects or complicated dosing regimen), and they may therefore differ from patients who continue to use the initially prescribed medication in ways related to adherence. Future research should examine whether switching between osteoporosis medications has an impact on the risk of fracture because of the effect of switching on adherence, as well as whether switching is associated with the risk of fracture independent of adherence.
Fourth, a pharmacy claim for a filled prescription does not claim (i.e., their index date claim) for an osteoporosis therapy. We excluded 2,372 commercial patients and 1,037 Medicare Advantage patients from the study sample for this reason. Although women who stopped osteoporosis therapy after their initial fills were part of a "real-world" population, we limited the study sample to women with a minimum threshold of osteoporosis therapy exposure (at least 2 pharmacy claims) because of the focus on fracture, while retaining variation in adherence and sufficient population size. Generalizability of these study results is, therefore, somewhat limited. Third, we included patients who used multiple osteoporosis The Association of Adherence to Osteoporosis Therapies with Fracture, All-Cause Medical Costs, and All-Cause Hospitalizations: A Retrospective Claims Analysis of Female Health Plan Enrollees with Osteoporosis

DISCLOSuRES
This study was funded by Amgen, and 3 of the authors (Iqbal, Macarios, and Badamgarav) are employed by Amgen. The sponsor Amgen took an active role in writing and revision of this manuscript and therefore had influence over the decision to publish this manuscript. Portions of the data in this study were presented in 2 posters at the 31st Annual Meeting of the American Society for Bone and Mineral Research in Denver, Colorado, on September 12-13, 2009, but the data presented in this final revised manuscript have not been presented previously.
indicate that the medication was consumed as prescribed. Fifth, MPR is measured over a designated period; for example, a patient observed over 1 year could have an MPR of 0.50 if she were (a) fully adherent over the first 6 months of observation and fully nonadherent over the second 6 months, (b) fully nonadherent over the first 6 months and fully adherent over the second 6 months, or (c) adherent and then nonadherent in alternating months. The analyses that examined the relationships between adherence and medical costs and inpatient hospitalizations do not allow us to make distinctions or draw inferences about variations in the effects of different patterns of adherence. The fracture regressions accounted for changing adherence through the use of time-dependent cumulative adherence, although the impact of different patterns of adherence cannot be interpreted from the HRs.
Sixth, not all osteoporosis therapies were included in this analysis: hormone replacement therapy was not included as an index therapy because its use was decreasing during the study period.

■■ Conclusions
To our knowledge, this is the first study that has examined the impact of osteoporosis therapies on fractures, medical costs, and hospitalizations across both commercial and Medicare populations. The results were largely consistent with the literature and corroborate results highlighting the importance of achieving and maintaining treatment adherence to receive the therapeutic and economic benefits of osteoporosis therapy. Future research should explore the relationship between adherence and osteoporosis-related outcomes, fracture sequelae and related costs, and osteoporosis-related costs over longer lengths of follow-up.